OTHER PROJECT INFORMATION - ITEM 7 - PROJECT SUMMARY/ABSTRACT: N-Acylethanolamine-hydrolyzing acid amidase (NAAA) is a lysosomal enzyme, which plays a central role in the deactivation of N-palmitoylethanolamine (PEA). PEA is an endogenous lipid produced on-demand synthesis by most mammalian cells and a growing body of evidence links PEA in the regulation of inflammatory and pain processes. We are the first to show and validate in animal models of ulcerative colitis that our in-house NAAA inhibitor AM9053 ameliorates all signs of colon inflammation in mice. Notwithstanding its promising pharmacological profile, AM9053 lacked the desired pharmacological profile for advancing to candidate developed advancement due to poor liver microsomal stability and limited oral bioavailability, thus, requiring the discovery and development of new optimized analogs with suitable druggability properties. During the Phase I program, we have identified two new series of potent and selective NAAA inhibitors in collaboration with the Center for Drug Discovery (CDD) at Northeastern University. In this application, we propose to fully optimize ligand potency, selectivity and compound druggability properties with the expectation to identify 2-3 candidates for advancement as development candidates for the treatment of ulcerative colitis. Our design is aided by computer and biophysical modeling techniques, aimed at optimizing the pharmacophoric features of the proposed analogs. We expect this optimization to be an ongoing iterative effort in which data from early results are elaborated using our ligand design concepts. We will also investigate the potential pharmacological role and advantages of NAAA inhibitors acting locally at the gut as novel therapies for GI inflammatory conditions. GI restricted treatments may offer advantages as safer medicines for IDB illnesses by limiting systemic drug exposure. The significance of our work is that it may lead to the development of improved pharmacotherapies that could ease the high personal and societal costs associated with inflammatory diseases. The drug discovery effort aimed at discovering novel druggable NAAA inhibitors is a joint collaborative effort with the Center for Drug Discovery (CDD) at Northeastern University. CDD scientists have cloned, expressed and purified milligram amounts of NAAA, and developed fluorescence-based screening assays for drug assessment. We also collaborate with Professor Kokkotou, at Beth Israel Deaconess Medical Center, Div. of Gastroenterology (BIDMC, Harvard) to evaluate our compounds in preclinical animal models of ulcerative colitis. Professor Kokkotou will also asses our NAAA inhibitors in ex-vivo studies with mucosal explants from patients with IBD seeking an early proof-of-principle of NAAA inhibition in inflammatory conditions in IBD patients.